Opioid analgesics such as morphine are therapeutically useful, but their usage is strictly limited because of their side effects such as drug dependency and abuse. Thus, analgesics, with high effectiveness and reduced tendency in causing drug dependency, are desired. Considerable pharmacological and biochemical studies have been carried out to discover opioid peptides and opioid receptors. The discovery of the subtype of opioid receptor such as mu (μ), delta (δ), kappa (κ) in a variety of species, including human, has provided a beginning towards creating new analgesics. As a result of the belief that opioid analgesics such as morphine act as mu-receptor agonists, separating the action based on a kappa-receptor agonist from the action based on mu-receptor agonist has been investigated. Recently such kappa-selective agonists (kappa-agonists) have been reported from the above viewpoint for example, EMD-61753: A. Barber et al., Br. J. Pharmacol., Vol. 113, pp. 1317–1327, 1994. Some of the kappa agonists actually have been studied in clinical trials (Med. Res. Rev., Vol.12, p. 525, 1992).
U.S. Pat. Nos. 6,201,007 and 6,031,114 relate to certain pyrrolidinyl and pyrrolinyl ethylamine compounds and the salts thereof. These compounds are useful as kappa agonists, and have specific utilities as analgesic, anesthetic, anti-inflammatory or neuroprotective agents. The disclosure of each of the foregoing United States patents is incorporated herein in its entirety by reference.
Additionally, European Patent No. EP 0254545 B1 discloses a variety of ethylenediamine compounds which are related to the salts prepared by the present method. European Patent No. EP 0483580 B1 also discloses a variety of pyrrolidine compounds useful as analgesics, and International Patent Publication WO 96/30339, published Oct. 3, 1996, refers to a wide variety of pyrrolidinyl hydroxamic acid compounds as selective kappa-receptor agonists.
It has now been found that the anhydrous benzoic acid salt of (2S,3S)-3-hydroxy-N-{2-[N-methyl-N-4-(N-propylamino-carbonyl)phenyl]amino-2-phen-yl}-ethylpyrrolidine can be isolated in a crystalline form which has advantageous physical chemical properties which improve the ease of preparing a purified drug. In addition, it has been determined that the process of the present invention permits the formation of the monohydrate benzoic acid salt in a highly pure, crystalline form which is sufficiently stable, chemically and physically, to meet the requirements for preparing a clinically useful drug formulation.